This invention describes the use of 4-aryl-4-piperidinecarbinols in the treatment of neuropathic dysfunction and neuropathic pain.
Many people, including over three million in the United States alone, experience neuropathic dysfunction. Neuropathic pain associated with neuropathic dysfunction is defined as pain associated with damage or dysfunction of peripheral or central nervous system.
Neuropathic pain is considered a malfunction in the response to a pathologic process occurring along and within the nervous system nociceptive pathways and is a much more complex phenomenon than simple pain. Pain has been defined as xe2x80x9can unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage.xe2x80x9d
The most common types of conventional pain are associated with a response to a pathophysiologic process occurring within the tissues, such as inflammation, due to an ongoing injury or damage. The pain signal generates from intact primary afferent nerves that signal noxious events, or nociceptors. Nociceptors can be sensitized by release of algogenic agents (eg, protons, prostaglandins, bradykinin, serotonin, adenosine, cytokines, etc).
In contrast, neuropathic pain is associated with signals generated ectopically and often in the absence of ongoing noxious events by pathologic processes in the peripheral or central nervous system. This dysfunction is associated with common symptoms such as allodynia (pain evoked by normally nonpainful touch), hyperalgesia (abnormally intensive and long-lasting pain from a painful stimuli), intermittent abnormal sensations, and spontaneous, burning, shooting, stabbing, paroxysmal or electrical-sensations.
Neuropathic pain has been associated with sensory changes such as paresthesias (abnormal, intermittent but nonpainful sensations, perceived spontaneously or evoked by a stimulus) or dysesthesias (abnormal painful sensations that are spontaneous or evoked). Allodynia, hyperalgesia and hyperpathia are positive sensory phenomena as opposed to the negative sensory phenomena defined by anesthesia and hypoesthesia. Allodynia, which may be mechanical or thermal, is the painful response to an ordinarily non-noxious stimulus, such as one""s clothing, the mere movement of air, touch, or the nonpainful application of a cold or warm stimulus. Hyperalgesias are exaggerated pain responses to a mildly noxious mechanical or thermal stimulus. Hyperpathia may be characterized as a delayed and explosive pain response to a noxious, or at times, non-noxious stimulus.
Neuropathic pain may result from peripheral or central nervous system pathologic events (eg, trauma, ischemia, infections) or from ongoing metabolic or toxic diseases, infections or endocrinologic disorders (eg, diabetes mellitus, diabetic neurophathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitic neuropathy, HIV infection, herpes zosterxe2x80x94shingles and postherpetic neuralgia, etc), neuropathy associated with Guillain-Barrxc3xa9 syndrome, neuropathy associated with Fabry""s disease, entrapment due to anatomic abnormalities, trigeminal and other CNS neuralgias, malignancies, inflammatory conditions or autoimmune disorders (including demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjxc3x6gren""s syndrome), and cryptogenic causes (idiopathic distal small-fiber neuropathy). Other causes of neuropathic pain include exposure to toxins or drugs (such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities and amputations (including mastectomy). Neuropathic pain may also result from compression of nerve fibers, such as radiculopathies and carpal tunnel syndrome.
During neuropathic pain, ectopic activity causes a spontaneous discharge in the peripheral nervous system (PNS) pathways, or depending on the location and type of nerve injury, ectopic discharge also may originate in the dorsal-root-ganglion (DRG) cells of damaged afferent axons. Within the same DRG, cell bodies of uninjured axons may exhibit ectopic activity too. Within the central nervous system (CNS), hyperexcitability of the signaling neurons may arise, and other mechanisms that facilitate or distort afferent input are likely. Central mechanisms underlying chronic neuropathic pain are poorly understood. Neuroanatomic, neurophysiologic, and neurochemical changes all occur as a response to PNS or CNS injury. Central sensitization at a dorsal horn level, which is mediated in part via the N-methyl-D-aspartate (NMDA) receptor, is the best characterized change involved in the generation of this dysfunction.
Table 4 below sets out common causes of neuropathic dysfunction. Se generally: www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=536).
The treatment of neuropathic pain continues to be a difficult and often unsuccessful medical challenge. For years neuropathic pain has confounded scientists. Drugs for the treatment of standard pain are typically ineffective against neuropathic pain, the drugs for the treatment of neuropathic pain often have no effect on normal pain sensation. Traditional pain treatments, including powerful medications of last resort such as morphine and other opioid analgesics, useful in the treatment of severe pain, rarely alleviate neuropathic pain. The development of tolerance, psychic and physical dependence and potentially serious opioid side effects also limit the usefulness of opioids in treating dysfunction. Anti-inflammatory analgesics, including the Cox-2 inhibitors, lack the efficacy of opioid analgesics and produce other serious side effects including gastrointestinal bleeding and gastric erosion that limits their usefulness in treating neuropathic pain.
Starting in 1988, researchers began to identify animal models that mimic the clinical signs of neuropathic pain. For example, a rat with nerve injuries has been found to exhibit a super-sensitive reaction to a hair tapped on its hindpaw. The rat will quickly jerk away. Some humans with neuropathic pain experience a similarly severe reaction. For them, the tickle of a hair can translate into a long lasting, burning sensation. The animal models of the ailment are helping scientists understand the underlying mechanism of neuropathic pain.
Drugs that have been investigated for the use to treat neuropathic pain include sodium channel antagonists, calcium channel supressors, N-methyl-D-aspartate (NMDA) receptor blockers, anticonvulsant medications, and oral tricyclic antidepressants.
Neurons have many calcium channels, including the high-conductance channel found in the NMDA receptor. Some participate in triggering the release of neurotransmitter from presynaptic vesicles. In chronic constriction injury (CCI) rats, calcium channels are known to affect the spontaneous discharge of injured nociceptive afferents (FIG. 2). However, the drug also exerts its well-known effects on calcium channels in cardiovascular muscle, and the dosages that relieve pain are at or above those causing unacceptable heart-rate and blood-pressure changes.
However, among the many varieties of calcium channels, at least one, the N-type, a voltage-gated channel, occurs only on neurons, not on cardiovascular muscle. In the Philippines, and subsequently at the University of Utah, B. M. Olivera and colleagues studied the venom of poisonous marine snails of the genus Conus. Among hundreds of snail species throughout the Indian and Pacific Oceans, a few survive by hunting fish. Waving a long proboscis, they evidently create the impression of a worm. When a fish investigates, the snail employs the proboscis to sting the fish in the gills. In this way, it introduces a poison directly into the fish""s cardiopulmonary circulation. The fish drops dead on the spot. Fractionating this powerful venom, the researchers found it to be a collection of small peptides, each consisting of 13 to 29 amino acids.
Among these substances (classified as omega-conopeptides), the researchers found one that affects the N-type calcium channel. A synthetic replica of a compound from the fish-paralyzing snail venom is one agent that offers relief in these animal models and now also appears to benefit humans. New human studies indicate that low doses of the agent cause minimal side effects and offer relief for patients with neuropathic pain. Under the name SNX-111, it has been synthesized by a biotechnology firm. When applied to the site of sciatic-nerve injury in CCI rats, the treatment reduced heat hyperalgesia and mechanical allodynia for at least three hours, but had no effect on mechanical hyperalgesia. Application to normal nerve had no effect on the animals"" responses to any sensory stimuli, thermal or mechanical. Hence, the relief did not represent any anesthetic-like nerve block. Since the boluses were too small for any significant quantities to have diffused to the spinal cord, presynaptic blockade of neurotransmitter release within the dorsal horn was not a tenable explanation, either. Most probably, the SNX compound had reduced spontaneous discharge in primary afferent fibers at and near the site of nerve damage. However, patients cannot take the drug orally, because the stomach digests these agents before they are able to reach the calcium entryways. Instead, physicians administer the agent directly into the spinal cord during a hospital visit. SNX-111 is administered by an implanted pump and catheter that delivers it directly to the lumbar spinal cord.
Other promising agents that can be consumed in pill form incapacitate areas on cells called N-methyl-D-aspartate (NMDA) receptors. Animal models have helped researchers uncover evidence that these receptors share a special relationship with neuropathic pain. It appears that continuous activation of NMDA receptors reorganizes pain-sensing circuits and leads to the super-sensitive quality of neuropathic pain. In a range of animal models studied in numerous laboratories, several different NMDA receptor blockers have significantly reduced neuropathic pain. Limited data amassed from human volunteers suggest a similar effect. Among the drugs is dextrorphan, known pharmacologically as the primary metabolite of the over-the-counter cough suppressant dextromethorphan. When dextrorphan was tested in CCI rats, an intraperitoneal dosage of 25 mg/kg was beneficial against heat hyperalgesia, where it normalized the latency of the withdrawal reflex on the nerve-injured side, but had no effect against mechanical allodynia and caused no changes on the animals"" control side.
However, unlike a neurotransmitter receptor that binds acetylcholine or serotonin, the NMDA receptor has binding sites not only for neurotransmitter (glutamate) but also for many other ligands, which modifies the receptor""s responsiveness. Indeed, glutamate has no effect unless other conditions are met. The first of these conditions involves a glycine binding site. If the site is unoccupied, the receptor remains inactive. Throughout the CNS, however, the extracellular concentration of glycine seems perennially sufficient to saturate the site. A further hurdle involves magnesium ions. The receptor incorporates a high-conductance ion channel, which in turn can bind Mg2+. The binding is voltage-sensitive. If the cell membrane is at its resting bioelectric potential, the ion stays in place, preventing other ions from passing. If, however, the cell has been excited by other inputs, so that the membrane is partially depolarized, the Mg2+ is released and ionic currents can flow. The partial depolarization can be accomplished by the cell""s excitatory inputs, which, for a dorsal-horn neuron, may include glutamate (received at non-NMDA receptors), acetylcholine, and, among peptide neurotransmitters, substance P and calcitonin gene-related peptide. Inhibitory influences are a similarly long list, including GABA (from local inhibitory neurons), norepinephrine and serotonin (from the brain), and, among neuropeptides, dynorphin and enkephalin. Presumably, exogenous Mg2+ keeps NMDA receptors unresponsive to glutamate. Only with glycine present and the membrane partially depolarized, the binding of glutamate to the NMDA receptor can have an effect. The opened ion channel conducts not only Na+, which enters the cell, and K+, which leaves, but also Ca2+, which enters.
Because the receptors are important components of a variety of circuits in the brain and spinal cord that carry out different mental functions, blocking their activity also has side effects, such as clouded thinking. The NMDA receptor occurs at a high density in the cerebral cortex and hippocampus. In consequence, drugs that block the receptor can have psychological effects. One strategy has been to identify a relatively ineffective blocker, such that normal mental activity involving NMDA receptors may represent low-frequency discharge at the brain""s NMDA synapses and hence may not be affected by a weak receptor blockade. In contrast, neuropathic pain may represent high-frequency discharge, which might be blunted even by a blocker with low affinity for the receptor. Another strategy has been to identify usable differences among NMDA receptor subtypes. So far, at least five have been identified, among which one appears to show a high concentration only in the spinal cord. A drug specific for this spinal subtype might avoid side effects arising from engagement of the brain""s NMDA receptors.
In certain respects, epilepsy resembles neuropathic pain. Injured sensory fibers may discharge spontaneously, though with a clocklike regularity unlike the irregular pattern of an epileptiform burst in cortical neurons. In both cases, the discharge is probably due in part to abnormal distribution or activation of voltage-gated sodium channels at the neuronal cell-surface membrane. Therefore, the standard anticonvulsant carbamazepine has been used against neuropathic pain, in particular, tic douloureux, which is one of the rarest of neuropathic syndromes. Against neuropathic pain, as against epilepsy, the drug is thought to have dual modes of action: blockade of sodium channels (in the manner of lidocaine) along with potentiation of GABAergic neurotransmission (in the manner of a barbiturate). Cells utilizing GABA as their inhibitory neurotransmitter are known to affect the dorsal-horn neurons that receive primary sensory afferents and emit ascending fibers. In both neuropathic pain and epilepsy, use of the drug has been impeded by the need to monitor liver function.
New generations of anticonvulsant medications, in particular felbamate, were found to be effective against abnormalities involved in neuropathic pain, at least as modeled in CCI rats. Felbamate is implicated in a voltage-gated sodium-channel blockade, a slight potentiation of GABAergic neurotransmission, and NMDA receptor blockade (owing to its capacity to bind not only glutamate but also NMDA). Nociceptive C fibers are known to use glutamate to signal dorsal-horn neurons, which express NMDA receptors (along with other known types of glutamate receptor). At intraperitoneal doses of up to 600 mg/kg (the drug""s antiepileptic range in rats), the high doses completely abolished abnormal sensations in the four measurable ways: heat hyperalgesia, mechanical hyperalgesia, mechanical allodynia and hindpaw guarding. Heat hyperalgesia was tested by noxious heat to the hindpaw. Mechanical hyperalgesia was tested by the tip of a safety pin, pushed slowly until it dimpled the hindpaw skin. Mechanical allodynia was tested by von Frey hairs. All effects lasted two to 12 hours. In the control hindpaw, all responses were unaffected, indicating that the drug acted specifically against neuropathic pain, rather than being broadly analgesic. With only limited solubility in intrathecal media, felbamate could not be tested directly for a spinal site of action. However, the U.S. Food and Drug Administration found that felbamate had been found to cause liver failure and aplastic anemia, sometimes fatally, in humans.
Anticonvulsants, gabapentin and lamotrigine, have been widely used for several years. In CCI rats, gabapentin was tested both intraperitoneally (at 10 to 75 mg/kg) and intrathecally (to the lumbar spinal cord, at 37.5 to 150 mcg/kg). At two and four hours, the intraperitoneal injections suppressed heat hyperalgesia and mechanical allodynia. In some instances, the suppression of heat hyperalgesia was complete. Against mechanical hyperalgesia, the drug lacked effect. At 24 hours, abnormal responses had returned. For the intrathecal injections, the pattern was similar, implying a spinal site of drug action. On the control side, gabapentin, like felbamate, caused no significant change in any responses. Chemically, gabapentin is a small, cyclic GABA analogue. Curiously, it has no direct effect on GABA receptors. Indirect effects have been proposed, for example, an upregulation of intracellular GABA storage. Gabapentin binds with high affinity to a subunit of a voltage-gated calcium channel distributed unevenly throughout the nervous system. It remains uncertain precisely which types of calcium channel have the subunit.
It is widely accepted that oral tricyclic antidepressants (TCAs) are useful adjuncts in treating neuropathic pain. In addition, tricyclic antidepressants may be better tolerated than anticonvulsants. While tricyclic antidepressants are not recognized as primary agents to treat neuropathic pain, TCAs have an effect of serotonin (5-HT) release, the noradrenergic pathways and a sodium channel blocking effect (S. Butler, Adv. Pain Res. Ther. 7:173-197, 1984), with evidence of efficacy existing for amitriptylin, imipramine, desimipramine and clomipramine. This effect is independent of their antidepressant effect and may be dose related. In fact, there is a lack of evidence for efficacy of selective serotonin reuptake inhibitors (SSRI) antidepressants for treating neuropathic pain. Recent work has highlighted a potential effect of topical doxepin, a TCA, in neuropathic pain. The topical application of doxepin is associated with few side effects, and particularly central side-effects.
Venlafaxine has been clinically evaluated for painful diabetic neuropathy (See for example, Pernia, A.; Mico, J. A.; Calderon, E.; Torres, L. M. xe2x80x9cVenlafaxine for the treatment of neuropathic painxe2x80x9d J Pain Symptom Manage, 2000, 19(6):408-10; Kiayias, J. A.; Vlachou E. D.; Lakka-Papadodima, E. xe2x80x9cVenlafaxine HCl in the treatment of painful peripheral diabetic neuropathyxe2x80x9d Diabetes Care, 2000, 23(5):699; Ansari, A. xe2x80x9cThe efficacy of newer antidepressants in the treatment of chronic pain: a review of current literaturexe2x80x9d Harv Rev Psychiatry 2000; 7(5):257-77; and Davis, J. L.; Smith, R. L. xe2x80x9cPainful peripheral diabetic neuropathy treated with venlafaxine HCl extended release capsulesxe2x80x9d Diabetes Care 1999, 22(11):1909-10).
Despite the research on neuropathic pain to date, very few therapies have been identified that are not associated with significant negative side effects. The research has been made more difficult by the inability to extrapolate success in conventional pain therapy to successful treatment of neuropathic dysfunction and associated pain. Because of neuropathic pains"" distinct pathophysiology and response to pharmacotherapy, the FDA considers xe2x80x9cneuropathic painxe2x80x9d, a unique and stand-alone indication, separate from xe2x80x9cchronic pain,xe2x80x9d xe2x80x9carthritis pain,xe2x80x9d xe2x80x9cmigraine pain,xe2x80x9d and xe2x80x9cacute pain.xe2x80x9d Certain 4-arylpiperidinecarbinols are known to have antidepressant activity. These compounds and methods for preparing them are disclosed in Ciganek, U.S. Pat. No. 4,485,109, issued Nov. 27, 1984 (E.I. DuPont de Nemours and Company).
4-Aryl-4-piperdine (or pyrrolidine or hexahydroazepine)carbinols and heterocyclic analogs, including 4-(3-thienyl)-xcex1,xcex1,1-trimethyl-4-piperidinemethanol, are disclosed in U.S. Pat. Nos. 5,019,650 and 5,086,063 as compounds useful in the treatment of depression and conventional pain.
U.S. Pat. No. 3,108,111 to Stern et al., Nov. 22, 1963, discloses piperidine compounds useful as cough suppressants and analgesics.
U.S. Pat. No. 3,080,372 to Janssen, Mar. 5, 1963, discloses pharmaceutically useful piperidines.
JP 5,9106-460-A discloses antifungal and analgesic nitrogen containing heterocycles, including piperidines.
BE 775,611 discloses 1-(3,3-diphenyl-1-propyl)-4-arylpiperidines as analgesics, spasmolytics and antitussive agents.
Several secondary piperidinecarbinols have been reported in the literature. Representative of these are M. A. Iorio et al., Tetrahedron, 4983 (1971); F. Bergel et al., J. Chem. Soc., 26, (1944); A. D. MacDonald et al., Brit J. Pharmacol., 1,4 (1946); A. L. Morrison et al., J. Chem. Soc., 1467, (1950); H. Kagi et al., Helv. Chim. Acta, 7,2489 (1949); U. Bondesson et al., Drug Metab. Dispos., 9,376 (1981); U. Bondesson et al., Acta Pharm. Suec., 11, 1 (1980).
Given that neuropathic disorders are chronic, extremely disabling and refractory to currently available analgesics, it would be of great benefit to provide new compositions and methods for its treatment.
Therefore, it is one object of the present invention to provide pharmaceutical compositions for the treatment of neuropathic disorders and associated dysfunction and pain.
It is another embodiment of the present invention to provide methods and uses of compounds and compositions for the treatment of neuropathic pain.
It has been discovered that 4-(3-thienyl)-xcex1,xcex1,1-trimethyl-4-piperidinemethanol (the compound of formula III, also referred to herein as compound A or EN 3215) or its pharmaceutically acceptable salt or prodrug is a superior compound for the treatment of neuropathic pain, and thus can be used to treat a patient suffering from any symptom arising from this dysfunction. Unlike opioid analgesics, it does not show significant activity at mu, kappa, delta or sigma receptor sites in the brain. Studies in animals show that it lacks the addictive and respiratory depressant properties of narcotic-related analgesics. Unlike anti-inflammatory analgesics, it does not inhibit prostaglandin synthesase activity or show anti-inflammatory effects in vivo. Like the tricyclic antidepressants, it inhibits uptake of serotonin, norepinephrine and/or dopamine in rat brain preparations. Effective doses of the compound of the invention for the treatment of neuropathic pain are not accompanied by significant anticholinergic side effects, sedation or other signs of motor impairment observed with tricyclic antidepressants.
In another embodiment, a compound of the formula (I) is provided for the treatment of neuropathic pain: 
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 1, 2 or 3;
R1 is CH3, C2H5, nxe2x80x94C3H7 or allyl;
R2 and R3 independently are H or alkyl of 1-4 carbon atoms; or R1 and R2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R2 and R3 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;
R4 is:
(a) phenyl or 
xe2x80x83wherein X is one or two substituents, the same or different, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
(b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
(d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF3;
R5 is alkyl of 1-4 carbon atoms, or is taken together with R6 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms;
R6 is H, alkyl of 1-4 carbon atoms, or is taken together with R5 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and
R7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon atoms, or xe2x80x94CH2phenyl; or
a pharmaceutically salt or N-oxide thereof, provided that when
1) R1, R5 and R6 are methyl, and R2 and R3 are H, then R4 is not 3,4-F2C6H3, 3,4-Cl2C6H3, p-t-butylphenyl, 2,3-(MeO)2C6H3, 2,5-(MeO)2C6H3, or 3-pyridyl;
2) R1 R5 and R6 are methyl or R5 and R6 are taken together as xe2x80x94(CH2)6xe2x80x94 and xe2x80x94(CH2)7xe2x80x94, then R4 is not 3-(MeO)C6H4.
Also provided is a novel class of carbinols useful for the treatment of neuropathic pain, having the formula (II): 
wherein
when m is 2 and R6 is other than H, R1 R2 and R3 are as defined above;
R4 is:
(a) 
(b) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms.
(c) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms,
(d) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or
(e) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF3;
R5 independently is alkyl of 1-4 carbon atoms or when taken together with R6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
R6 independently is alkyl of 1-4 carbon atoms, or when taken together with R5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
R7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or xe2x80x94CH2phenyl; and
when m is 1 or 3, or when R6 is H and m is 2; then R1 independently is CH3, C2H5, nxe2x80x94C3H7, or allyl;
R2 and R3 independently are H or alkyl of 1-4 carbon atoms; or R1 and R2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;
or R2 and R3 taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;
R4 is:
(a) phenyl or 
xe2x80x83where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
(b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
(d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF3;
R5 independently is alkyl of 1-4 carbon atoms, or when taken together with R6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
R6 independently is H, alkyl of 1-4 carbon atoms, or when taken together with R5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
R7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or xe2x80x94CH2phenyl; or
a pharmaceutically suitable salt or N-oxide thereof,
provided that when R6 is H, R1 is methyl and m is 2, then R4 is other than C6H5, 2-(MeO)C6H4, 2,3-(MeO)2C6H3 and pharmaceutically suitable salts or N-oxides thereof.
Preferred compounds are those of Formula (1) where when m is 2:
(a) R1 is CH3; or
(b) R2 and R3 are H; or
(c) R4 is 2- or 3-thienyl, or 
xe2x80x83where X is Cl, Br, F, CF3; or
(d) R5 is CH3; or
(e) R6 is H or CH3; or
(f) R7 is H.
Preferred compounds are those of Formula (I) where when m is 1 or 3;
(a) R1 is CH3; or
(b) R2, R3 and R7 are H; or
(c) R4 is 
xe2x80x83where X is Cl, Br, F or CF3; or
(d) R5 is CH3; or
(e) R6 is H or CH3.
Specifically preferred compounds are the following:
(a) 4-(3xe2x80x2-Thienyl)-xcex1,xcex1,1-trimethyl-4-piperidinemethanol;
(b) 4-(3xe2x80x2-Chlorophenyl)-xcex1,1-dimethylpiperidinemethanol;
(c) 4-(3xe2x80x2-Chlorophenyl)-xcex1,xcex1,1-trimethyl-4-piperidinemethanol;
(d) 4-(3xe2x80x2-Bromophenyl)-xcex1,1-dimethylpiperidinemethanol;
(e) 4-(3xe2x80x2-Bromophenyl)-xcex1,xcex1,1-trimethyl-4-piperidinemethanol;
(f) 4-(2-Thienyl)-xcex1,1-dimethylpiperidinemethanol;
(g) 4-(3-Thienyl)-xcex1,1-dimethylpiperidinemethanol;
(h) 4-(3xe2x80x2-Chlorophenyl)-xcex1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol;
(i) 3-(3xe2x80x2-Chlorophenyl)-xcex1,xcex1,1-trimethyl-3-pyrrolidinemethanol; and
(j) 4(4xe2x80x2-Trifluoromethylphenyl)-xcex1-1-dimethylpiperidinemethanol
or a pharmaceutically suitable salt thereof.
Also provided is a compound having the formula (III): 
or its pharmaceutically acceptable salt or prodrug thereof, for the treatment or prophylaxis of neuropathic pain.
Alternatively, provided is a compound having the formula (IV): 
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
X1 and X2 are independently O or NR2; and
R1 is H, alkyl, lower alkyl (such as a C1 to C6 optionally substituted branched or straight-chained alkyl); alkenyl, alkynyl, acyl, xe2x80x94C(O)R5, xe2x80x94C(O)NR5R6, xe2x80x94C(O)OR5, xe2x80x94C(O)SR5, xe2x80x94C(S)R5, xe2x80x94C(S)NR5R6, xe2x80x94C(S)OR5, xe2x80x94C(S)SR5, xe2x80x94C(NR7)R5, xe2x80x94C(NR7)NR5R6, xe2x80x94C(NR7)OR5, xe2x80x94C(NR7)SR5 or phosphate; and
R2, R5, R6 and R7 are independently H, alkyl or lower alkyl (such as a C1 to C4 optionally substituted branched or straight-chained alkyl).
In one embodiment of the present invention, a compound of formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, are used for the treatment or prophylaxis of neuropathic disorders and associated dysfunction and neuropathic pain.
In another embodiment of the invention, compositions comprising compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, in combination with one or more other agents are useful for the treatment of neuropathic pain.
In another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compound of formula (I)-(IV).
In yet another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compound of formula (I)-(IV) in combination or alternation with one or more other active agents.
In yet another embodiment, a use of compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, and optionally in combination or alternation with one or more other agents for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain is provided.
In yet another embodiment, a use of compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, optionally in combination or alternation with one or more other agents in the manufacture of a medicament for the treatment or prophylaxis of neuropathic pain is provided.